We have proposed that orosomucoid (alpha 1-acid glycoprotein) deficiency in plasma is a cause of hyperlipidemia in nephrosis in which orosomucoid is lost in the urine. We have established that orosomucoid functions as a co-factor in the lipoprotein lipase enzyme system which is involved with clearance of chylomicrons and very low density lipoproteins. In a nephrotic rat model, plasma triglycerides and cholesterol are markedly elevated. These rats show defective removal of an injected triglyceride emulsion and a 10 fold increase in hepatic HMG-CoA reductase, the key enzyme on cholesterol synthesis. Injection of orosomucoid into these rats restores triglyceride removal mechanisms to normal. We propose to: 1. carry out a clinical study of the correlation of plasma orosomucoid levels and plasma triglycerides and cholesterol in nephrotic patients, diabetes with nephropathy and uremic patients on peritoneal dialysis and the appropriate control groups. 2. study the mechanism of orosomucoid action in the clearance of chylomicrons and VLDL in normal and nephrotic rats and in liver cell systems. 3. define the chemical nature of the orosomucoid molecule which determines the "active" and "inactive" forms in a lipoprotein lipase assay system. 4. investigate the mechanism of the action of orosomucoid on the lipoprotein lipase reaction and its influence on the kinetics of this complex enzyme system. 5. investigate the participation of orosomucoid in generating an effector which inhibits cholesterogenesis in primary hepatocyte culture systems. 6. develop preparative methods for the isolation of "active" orosomucoid from human plasma for potential use in replacement therapy.